Oncolytic Virus for the Therapy of Pancreatic Adenocarcinoma

As many other cancers, pancreatic ductal adenocarcinoma (PDAC) progression is associated with a series of hallmark changes for cancer cells to secure their own growth success. Yet, these very changes render cancer cells highly sensitive to viral infection. A promising strategy may rely on and exploit viral replication for tumour destruction, whereby infection of tumour cells by a replication-conditional virus may lead to cell destruction and simultaneous release of progeny particles that can spread and infect adjacent tumour cells, while sparing healthy tissues. In the present study, we used Myb34.5, a second-generation replication-conditional HSV-1 mutant in which ICP6 gene expression is defective and expression of the HSV-1 ?134.5 gene is regulated by the cellular B-myb promoter. We found that B-myb is present in experimental PDAC and tumours, and is over expressed in patients’ tumours, as compared to normal adjacent pancreas. Myb34.5 replicates to high level in human PDAC cell lines and is associated with cell death by apoptosis. In experimental models of PDAC, mice receiving intratumoral Myb34.5 injections appeared healthy and tumour progression was inhibited, with evidences of tumour necrosis, haemorrhage, viral replication and cancer cell death by apoptosis. Combining standard-of-care chemotherapy with Myb34.5 successfully led to a very impressive antitumoral effect that is rarely achieved in this experimental model, and resulted in a greater reduction in tumour growth than chemotherapy alone. These promising results warrant further evaluation in early phase clinical trial for patients diagnosed with PDAC for whom no effective treatment is available.